Autophagy is a homeostatic process highly conserved in eukaryotic cells where it acts as a cytoplasmic biomass quantity and quality control system (Mizushima et al., 2008; Yang and Klionsky, 2010). Its functions encompass programmed cell survival and cell death, normally skewed toward cell survival (Kroemer and Levine, 2008) through provision of energy and nutrients and ridding the cytoplasm of toxic macromolecular aggregates, faulty organelles (Mizushima et al., 2008; Yang and Klionsky, 2010) and invading microorganisms (Deretic and Levine, 2009; Levine et al., 2011).
The cell-autonomous antimicrobial defense functions of autophagy, demonstrated initially in the case of streptococci (Nakagawa et al., 2004) and Mycobacterium tuberculosis (Gutierrez et al., 2004; Harris et al., 2007; Ponpuak et al., 2010), have been extended to a wide variety of microbes with a caveat that most highly adapted pathogens have evolved specific protective mechanisms against autophagic elimination of microbes (Deretic and Levine, 2009; Gannage et al., 2009; Kyei et al., 2009; Lee et al., 2009; Orvedahl et al., 2007; Yoshikawa et al., 2009). Other studies have uncovered orderly intersections between autophagy and innate (Chaturvedi et al., 2008; Cooney et al., 2010; Delgado et al., 2008; Huang et al., 2009; Sanjuan et al., 2007; Shi and Kehrl, 2010; Tang et al., 2010; Travassos et al., 2009; Xu et al., 2007; Yano et al., 2008) and adaptive immunity (Blanchet et al., 2010; Lee et al., 2010; Munz, 2009; Nedjic et al., 2008; Paludan et al., 2005), T cell development, differentiation and homeostasis (Jia and He, 2011; Nedjic et al., 2008), and inflammatory responses (Cadwell et al., 2010; Jounai et al., 2007; Levine et al., 2011; Saitoh and Akira, 2010). Autophagy suppresses endogenous, cell-autonomous promoters of inflammation (Mathew et al., 2009; Orvedahl et al., 2010).
Specific autophagic factors, such as Atg5-Atg12, have been shown to inhibit RIG-I signaling (Jounai et al., 2007) whereas Atg9, have been reported to negatively regulate trafficking, assembly and activation of TBK-1 (TANK-binding kinase 1), which, among its key functions, controls type I interferon response elicited by intracellular double stranded DNA (Saitoh et al., 2009). In the context of anti-inflammatory function, recent studies indicate that autophagy plays an inhibitory role in inflammasome and IL-1β activation by mechanisms that involve mitochondrial homeostasis (Nakahira et al., 2010; Zhou et al., 2011) or potentially direct effects (Harris et al., 2011). Finally, a number of genetic links have been found in human populations between autophagy and idiopathic inflammatory (Consortium, 2007; Craddock et al., 2010) or infectious diseases such as tuberculosis (Che et al., 2010; Intemann et al., 2009; Singh et al., 2006; Singh et al., 2010), with significant inflammatory components and tissue damage.
Given the interconnectedness of autophagy and immunity, it is likely that the immune manifestations of autophagy are affected not only by the induction of autophagy but also by the completion of the autophagic pathway. The formation of the autophagic organelles of the sensu stricto autophagy pathway (also referred to as macroautophagy) depends on multiple sources of membrane or regulatory factors (Tooze and Yoshimori, 2010). The key stages of autophagy however are not restricted to the formation of autophagosomal membranes and include the sequestration of the earmarked cargo by the autophagic adaptors (Bjorkoy et al., 2005; Kirkin et al., 2009; Thurston et al., 2009; Wild et al., 2011), and the less understood process of the maturation of autophagic organelles into autolysosomes where the captured material is degraded (Korolchuk et al., 2011; Liang et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009).
Thus, autophagy is directly implicated in cancer, type II diabetes, neurodegenerative syndromes such as Alzheimer's, Huntington's and Parkinson's diseases, chronic inflammatory diseases (e.g. Crohn's disease), type II diabetes, infections (such as tuberculosis and HIV (I and II)/AIDS, hepatitis B, hepatitis C), and a variety of disorders associated with aging. A better understanding of how autophagic mechanisms are implicated in the aforementioned diseases could prove critical to preventing or treating these maladies.
The references which are cited above are presented after Example 2 of the present specification.